SARS-CoV-2: Pathogenesis and Countermeasure Development

SARS-CoV-2：发病机制和对策开发

• 批准号: 10927956
• 负责人: Heinrich Feldmann
• 金额: $ 34.15万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927956
• 关键词: 2019-nCoV; Adult; Animal Disease Models; Animal Diseases; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antiviral Agents; Binding; Bronchial Diseases; COVID-19; COVID-19 treatment; COVID-19 vaccine; Cells; Cellular Tropism; Characteristics; Chronic Obstructive Pulmonary Disease; Clinical; Containment; Cytology; Data; Development; Disease; Disease Progression; Disease model; Dose; Drug Compounding; Drug usage; Emergency Situation; Emerging Communicable Diseases; Fostering; Functional disorder; Funding; Goals; Goblet Cells; Hamsters; Human; Hyperplasia; Immune response; Immunity; Immunize; Individual; Infection; Inflammatory; International; Intramuscular; Investigation; Lower respiratory tract structure; Lung; Macaca; Macaca mulatta; Macaca nemestrina; Manuscripts; Mesocricetus auratus; Microbe; Modeling; Mucous Membrane; Mus; Nasal cavity; National Institute of Allergy and Infectious Disease; Oral; Pathogenesis; Pathogenicity; Pathology; Pharmaceutical Preparations; Play; Population; Preparation; Protease Inhibitor; Public Health; Pulmonary Pathology; RNA replication; RNA vaccine; Recovery; Replicon; Reporting; Research; Respiratory Disease; Respiratory System; Risk; Role; SARS-CoV-2 B.1.1.529; SARS-CoV-2 B.1.617.2; SARS-CoV-2 BA.1; SARS-CoV-2 BA.2; SARS-CoV-2 immunity; SARS-CoV-2 infection; SARS-CoV-2 variant; Saimiri; Sampling; Severity of illness; Site; Structure of parenchyma of lung; Therapeutic; Tissues; United States National Institutes of Health; Update; Upper respiratory tract; Vaccinated; Vaccination; Vaccines; Variant; Viral; Viral Load result; Virus; Virus Diseases; Virus Replication; Virus Shedding; Work; airway epithelium; coronavirus disease; cytokine; disease transmission; drug candidate; drug repurposing; efficacy testing; high risk; immunogenicity; improved; in vivo; innovation; insight; molnupiravir; nasal swab; neutralizing antibody; nirmatrelvir; novel; nucleoside analog; pathogenic virus; programs; protective efficacy; receptor; respiratory; response; small molecule inhibitor; text searching; vaccine development; variants of concern

The global public health burden caused by SARS-CoV-2 and its resulting disease, COVID-19, has driven the rapid development of vaccines and treatment options. However, the continued emergence of novel SARS-CoV-2 variants of concern (VOC), which rapidly and globally replace earlier, previously predominant strains, and the diminished efficacy of current vaccines and certain treatments against infection by these VOC has raised concerns. Therefore, additional vaccine and therapeutic approaches are urgently needed. DMTs work had three major objectives: (i) Develop new and refine existing animal disease and infection models and study pathogenesis; (ii) repurpose existing drug compounds and evaluate their therapeutic potential in those animal models; (iii) develop vaccines and perform efficacy testing utilizing those animal models. Animal Models Program In 2020, we reported on the establishment of an intranasal Syrian hamster disease model for SARS-CoV-2 recapitulating mild to moderate human COVID-19. SARS-CoV-2 replication in the respiratory tract peaked within days with animals showing mild respiratory disease followed by complete recovery (Rosenke et al., Emerg Microbes Infect 2020). To avoid infection at a key virus replication site, we established an intramuscular infection model in Syrian hamsters. The model showed similar disease and replication characteristics, but the ID50 was about 3 log10 higher. Refinement for proper use of this disease model is still ongoing (Rosenke et al., manuscript in preparation). Since the emergence of SARS-CoV-2, multiple different variants of concern (VOCs) have been identified. Recently, we investigated disease progression in the rhesus macaque model upon inoculation with the Delta, Omicron BA.1, and Omicron BA.2 VOCs. Disease severity in rhesus macaques inoculated with Omicron BA.1 or BA.2 was lower than those inoculated with Delta and resulted in significantly lower viral loads in nasal swabs, bronchial cytology brush samples, and lung tissue in rhesus macaques. Overall, these data suggest that, in rhesus macaques, Omicron replicates to lower levels than the Delta VOC, resulting in reduced clinical disease (Rosenke et al., Sci Adv 2022). We are discontinuing our investigation into other animal species as disease/infection models. As a last report on this topic, we showed that squirrel monkeys are also not susceptible to SARS-CoV-2 (Okumura et al., in preparation). Chronic obstructive pulmonary disease (COPD) is one of the underlying conditions in adults that place them at risk for developing severe illnesses associated with COVID-19. To determine whether SARS-CoV-2's cellular tropism plays a critical role in severe lung pathophysiology, we investigated its host cell entry receptor distribution in the bronchial airway epithelium of healthy adults and high-risk adults. We found that SARS-CoV-2 preferentially infects goblet cells in the bronchial airway epithelium. SARS-CoV-2 replication was substantially increased in the COPD bronchial airway epithelium, likely due to COPD-associated goblet cell hyperplasia. Our results reveal that goblet cells play a critical role in SARS-CoV-2-induced pathophysiology in the lung. (Osan et al., Microbiol Spectr 2022) Therapeutic Program Early 2020, we started a therapeutic project focusing on repurposing drugs for use against SARS-CoV-2. We established a drug pipeline starting with literature search selecting potential drug candidates (Jarvis et al., Antivir Ther 2020). This work identified molnupioravir as a drug candidate. We next demonstrated potent in vivo efficacy of orally delivered molnupiravir in the hamster model (Rosenke et al., Nat Commun 2021; Rosenke et al., JCI Insight 2022). This supported the establishment of molnupiravir as a treatment for human COVID cases. During FY23 we tested the efficacy of two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-07321332), a 3C-like protease inhibitor, in the rhesus macaque model. Macaques were infected with the SARS-CoV-2 Delta variant and treated with vehicle, MK-4482, PF-07321332, or a combination of MK-4482 and PF-07321332. Notably, use of MK-4482 and PF-07321332 in combination improved the individual inhibitory effect of both drugs, resulting in milder disease progression, stronger reduction of virus shedding from mucosal tissues of the upper respiratory tract, stronger reduction of viral replication in the lower respiratory tract, and reduced lung pathology. Our data strongly indicate superiority of combined MK-4482 and PF-07321332 treatment of SARS-CoV-2 infections (Rosenke et al., JCI Insight 2023). Vaccine Program In FY23 we evaluated a novel self-amplifying replicon RNA vaccine against SARS-CoV-2 in a pigtail macaque model of COVID-19 disease. We found that this vaccine elicited strong binding and neutralizing antibody responses against homologous virus. We also observed broad binding antibody against heterologous contemporary and ancestral strains, but neutralizing antibody responses were primarily targeted to the vaccine-homologous strain. While binding antibody responses were sustained, neutralizing antibody waned to undetectable levels in some animals after six months but were rapidly recalled and conferred protection from disease when the animals were challenged after vaccination as evident by reduced viral replication and pathology in the lower respiratory tract, reduced viral shedding in the nasal cavity and lower concentrations of pro-inflammatory cytokines in the lung. Cumulatively, our data demonstrate that a self-amplifying replicon RNA vaccine can elicit durable and protective immunity to SARS-CoV-2 infection. Furthermore, these data provide evidence that this vaccine can provide durable protective efficacy and reduce viral shedding even after neutralizing antibody responses have waned. (OConnor et al., PLoS Pathog 2023) Studies have shown that SARS-CoV-2 Omicron (B.1.1.529) is less sensitive to protective antibody conferred by previous infections and vaccines developed against earlier lineages of SARS-CoV-2. The ability of B.1.1.529 to spread even among vaccinated populations has led to a global public health demand for updated vaccines that can confer protection against B.1.1.529. We rapidly developed a replicating RNA vaccine expressing the B.1.1.529 spike and evaluated immunogenicity in mice and hamsters. We also challenged hamsters with B.1.1.529 and evaluated whether vaccination could protect against viral shedding and replication within respiratory tissue. We found that mice previously immunized with A.1-specific vaccines failed to elevate neutralizing antibody titers against B.1.1.529 following B.1.1.529-targeted boosting, suggesting pre-existing immunity may impact the efficacy of B.1.1.529-targeted boosters. Furthermore, we found that our B.1.1.529-targeted vaccine provides superior protection compared to the ancestral A.1-targeted vaccine in hamsters challenged with the B.1.1.529 VoC after a single dose of each vaccine. Our data suggest that B.1.1.529-targeted vaccines may provide superior protection against B.1.1.529 but pre-existing immunity and timing of boosting may need to be considered for optimum protection. (Hawman et al., EBioMedicine 2022) Note, our work on SARS-CoV-2 will be discontinued as COVID emergency funding has ceased. We will finish the ongoing projects but, as of now, not starting new projects on SARS-CoV-2.

SARS-CoV-2及其引发的疾病COVID-19造成的全球公共卫生负担推动了疫苗和治疗方案的快速发展。然而，新型SARS-CoV-2关注变种（VOC）的持续出现，迅速并在全球范围内取代了早期的、以前占主导地位的菌株，以及当前疫苗和某些治疗方法对这些VOC感染的效力下降，令人担忧。因此，迫切需要更多的疫苗和治疗方法。

项目成果

Defining the Syrian hamster as a highly susceptible preclinical model for SARS-CoV-2 infection.

• DOI: 10.1080/22221751.2020.1858177
• 发表时间: 2020-12
• 期刊: Emerging microbes & infections
• 影响因子: 13.2
• 作者: Rosenke K;Meade-White K;Letko M;Clancy C;Hansen F;Liu Y;Okumura A;Tang-Huau TL;Li R;Saturday G;Feldmann F;Scott D;Wang Z;Munster V;Jarvis MA;Feldmann H
• 通讯作者: Feldmann H

SARS-CoV-2 reinfection prevents acute respiratory disease in Syrian hamsters but not replication in the upper respiratory tract.

• DOI: 10.1016/j.celrep.2022.110515
• 发表时间: 2022-03-15
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Hansen F;Meade-White K;Clancy C;Rosenke R;Okumura A;Hawman DW;Feldmann F;Kaza B;Jarvis MA;Rosenke K;Feldmann H
• 通讯作者: Feldmann H

Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model.

• DOI: 10.1172/jci.insight.160108
• 发表时间: 2022-07-08
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Rosenke, Kyle;Okumura, Atsushi;Lewis, Matthew C.;Feldmann, Friederike;Meade-White, Kimberly;Bohler, W. Forrest;Griffin, Amanda;Rosenke, Rebecca;Shaia, Carl;Jarvis, Michael A.;Feldmann, Heinz
• 通讯作者: Feldmann, Heinz

An Intramuscular DNA Vaccine for SARS-CoV-2 Decreases Viral Lung Load but Not Lung Pathology in Syrian Hamsters.

• DOI: 10.3390/microorganisms9051040
• 发表时间: 2021-05-12
• 期刊: Microorganisms
• 影响因子: 4.5
• 作者: Leventhal SS;Clancy C;Erasmus J;Feldmann H;Hawman DW
• 通讯作者: Hawman DW

A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques.

• DOI: 10.1016/j.xcrm.2021.100230
• 发表时间: 2021-04-20
• 期刊: Cell reports. Medicine
• 作者: Hassan AO;Feldmann F;Zhao H;Curiel DT;Okumura A;Tang-Huau TL;Case JB;Meade-White K;Callison J;Chen RE;Lovaglio J;Hanley PW;Scott DP;Fremont DH;Feldmann H;Diamond MS
• 通讯作者: Diamond MS